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(Circulation. 2002;105:502.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Restoration of Deficient Membrane Proteins in the Cardiomyopathic Hamster by In Vivo Cardiac Gene Transfer

Yasuhiro Ikeda, MD, PhD; Yusu Gu, MD; Yoshitaka Iwanaga, MD, PhD; Masahiko Hoshijima, MD, PhD; Sam S. Oh, BS; Frank J. Giordano, MD; Ju Chen, PhD; Vincenzo Nigro, MD; Kirk L. Peterson, MD; Kenneth R. Chien, MD, PhD; John Ross, Jr, MD

From the Department of Medicine, Division of Cardiology (Y. Ikeda, Y.G., Y. Iwanaga, M.H., S.S.O., J.C., K.L.P., K.R.C., J.R.) and Institute of Molecular Medicine (M.H., K.R.C., J.R.), University of California, San Diego, Calif; the Department of Internal Medicine (F.J.G.), Cardiology, Yale University, New Haven, Conn; and Istituto di Patologia Generale ed Oncologia (V.N.), Facoltà di Medicina, Seconda Università degli Studi Napoli, Italy.

Correspondence to John Ross Jr, MD, Dept of Medicine, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0613B. E-mail jross{at}ucsd.edu

Background— One of the most important problems in developing in vivo cardiac gene transfer has been low transfection efficiency. A novel in vivo technique was developed, tested in normal hamsters, and the feasibility of restoring a deficient structural protein (-sarcoglycan) in the cardiomyopathic (CM) hamster evaluated.

Methods and Results— Adenoviral (AdV) vectors encoding either the lacZ gene or -sarcoglycan gene were constructed. Hypothermia was achieved in hamsters by external body cooling to a rectal temperature of 18 to 25°C. Through a small thoracotomy, the ascending aorta and the main pulmonary artery were occluded with snares, and cardioplegic solution containing histamine was injected into the aortic root; viral constructs were delivered 3 to 5 minutes later followed by release of the occluders and rewarming. Four days later, homogeneous ß-galactosidase expression was detected throughout the ventricles of the normal hearts (average 77.3±9.0% [SEM] of left ventriclar myocytes). At 1 and 3 weeks after transfection, immunostaining showed extensive restoration of -sarcoglycan as well as - and ß-sarcoglycan proteins to the myocyte membranes, despite loss of ß-galactosidase expression at 3 weeks. Also, at 3 weeks after gene transfer, there was significantly less progression of left ventricular dysfunction assessed as percent change in fractional shortening compared with controls.

Conclusions— This study demonstrates the feasibility of high efficiency in vivo myocardial gene transfer and shows application in improving the level of a deficient cardiac structural protein and cardiac function in CM hamsters. The approach should be useful for assessing effects of expressing other genes that influence the structure or function of the normal and failing heart.

Key Words: gene therapy • cardiomyopathy • adenovirus

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